Abstract
The process of macrophage polarization is involved in many pathologies such as anti-cancer immunity and autoimmune diseases. Polarized macrophages exhibit various levels of plasticity when M2/M(IL-4) macrophages are reprogrammed into an M1-like phenotype following treatment with IFNγ and/or LPS. At the same time, M1 macrophages are resistant to reprogramming in the presence of M2-like stimuli. The molecular mechanisms responsible for the macrophages polarization, plasticity of M2 macrophages, and lack of plasticity in M1 macrophages remain unknown. Here, we explored the role of Egr2 in the induction and maintenance of macrophage M1 and M2 polarization in the mouse in vitro and in vivo models of inflammation. Egr2 knockdown with siRNA treatment fail to upregulate either M1 or M2 markers upon stimulation, and the overexpression of Egr2 potentiated M1 or M2 marker expression following polarization. Polarisation with M2-like stimuli (IL-4 or IL-13) results in increased Egr2 expression, but macrophages stimulated with M1-like stimuli (IFNγ, LPS, IL-6, or TNF) exhibit a decrease in Egr2 expression. Egr2 was critical for the expression of transcription factors CEBPβ and PPARγ in M2 macrophages, and CEBPβ was highly expressed in M1-polarized macrophages. In siRNA knockdown studies the transcription factor CEBPβ was found to negatively regulate Egr2 expression and is likely to be responsible for the maintenance of the M1-like phenotype and lack plasticity. During thioglycolate-induced peritonitis, adoptively transferred macrophages with Egr2 knockdown failed to become activated as determined by upregulation of MHC class II and CD86. Thus, our study indicates that Egr2 expression is associated with the ability of unstimulated or M2 macrophages to respond to stimulation with inflammatory stimuli, while low levels of Egr2 expression is associated with non-responsiveness of macrophages to their activation.
Highlights
It is accepted that at least two pathways for macrophage activation exist leading to two distinct or polarized states: the M1- and M2-like phenotypes [1, 2]
We hypothesized that Egr1, Egr2, and Egr3 play an important role in the regulation of macrophage activation toward M1- and/or M2-like phenotypes
We demonstrated an important role of Egrfamily proteins in macrophage activation driven by M1- or M2-like stimuli
Summary
It is accepted that at least two (among others) pathways for macrophage activation exist leading to two distinct or polarized states: the M1- and M2-like phenotypes [1, 2]. M1-like macrophages express a high level of MHC class II and CD86 and effectively stimulate CD4 T cells to drive strong pro-inflammatory properties [2, 5, 6]. These include the manufacture of NO (produced by enzyme NOS2) and the secretion of a number of potent proinflammatory cytokines such as IL-1β, IL-6, and TNF [2, 6]. M2-like macrophages are known to produce more anti-inflammatory cytokines including IL-10 and TGFβ1; IL-10 is not considerate to be a specific M2 marker but is probably more indicative of the presence of deactivated macrophages [2, 10]. The transcription factor PPARγ was recently shown to be involved in M2 polarization [6, 11], while its upstream transcription factor CEBPβ was shown to be necessary for the induction of both M1 and M2 markers upon stimulation with either M1 or M2 directing stimuli [2, 12,13,14,15]
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